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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 6, 2014

Positive Rules and Negative Ones

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Posted by Derek

I enjoyed this take on med-chem, and I think he's right:

There are a large set of "don't do this". When they predict failure, you usually shouldn't go there as these rules are moderately reliable.

There is an equally large set of "when you encounter this situation, try this" rules. Their positive predictive power is very very low.

Even the negative rule, the what-to-avoid category, aren't as hard as fast as one would like. There are some pretty unlikely-looking drugs out there (fosfomycin, nitroglycerine, suramin, and see that link above for more). These structures aren't telling you to go out and immediately start imitating them, but what they are telling you is that things that you'd throw away can work.

But those rules are still right more often than the "Here's what to do when . . ." ones, as John Alan Tucker is saying. Every experienced medicinal chemist has a head full of these things - reduce basicity to get out of hERG problems, change the logP for blood-brain-barrier penetration, substitute next to a phenol to slow glucuronidation, switch tetrazole/COOH, make a prodrug, change the salt, and on and on. These work, sometimes, but you have to try them every time before moving on to anything more exotic.

And it's the not-always-right nature of the negative rules, coupled with the not-completely-useless nature of the positive ones, that gives everyone room to argue. Someone has always tried XYZ that worked, while someone else has always tried XYZ when it didn't do a thing. Pretty much any time you try to lay down the law about structures that should or shouldn't be made, you can find arguments on the other side. The rule-of-five type guidelines look rather weak when you think about all the exceptions to them, but they look pretty strong when you compare them to all the other rules that people have tried, and so on.

In the end, all we can do is narrow our options down from an impossible number to a highly improbable number. When (or if) we can do better, medicinal chemistry will change a great deal, but until then. . .

Comments (8) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs


1. Anonymous on January 6, 2014 10:03 AM writes...

This falls under the category of "It's nice to know the rules and the exceptions, but if you only know one, it should be the rule..."

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2. mimac on January 6, 2014 10:04 AM writes...

Theese rules should be expanded from "don't to this" to "don't do this, because..." and equaly with the positive one. I believe that until we know why an introduced change worked better/worse it's all just a hit and miss game.

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3. LeeH on January 6, 2014 11:20 AM writes...

The problem is that the rules have some probability of working, but they are rules-of-thumb, not laws. Over a large number of applications, they will work with some frequency (often very high), but they will defintely fail with some frequency (1 - the other frequency). They are meant to be guiding principles, not handcuffs. Medicinal chemists have a hard time with this concept.

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4. @kayakphilip on January 6, 2014 12:07 PM writes...

I used to work under the idea of spending about 80% of my effort doing stuff that made sense, and 20% doing stuff that was more quirky or speculative or pushed the boundaries. My one compound that made it to the clinic came from the 20%. But as @JohnTuckerPhD says - almost certainly more luck than judgement.

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5. Hap on January 6, 2014 12:29 PM writes...


The problem is that the rules have some probability of working, but they are rules-of-thumb, not laws. Over a large number of applications, they will work with some frequency (often very high), but they will defintely fail with some frequency (1 - the other frequency). They are meant to be guiding principles, not handcuffs. Medicinal chemists have a hard time with this concept.

Medicinal chemists aren't the only ones with that particular problem, I think - the "impact factors = moral hazard" discussion highlights a similar problem. We look for ways to make the world fit within our intellectual grasp, and to make our jobs easier, or possible. Rules can help, as long as we keep their limitations (or the lack of knowledge of such) in mind. Of course, we don't like keeping our limitations in mind, either.

Perhaps there's no royal road to drug development, either? Management will be disappointed.

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6. SP on January 6, 2014 2:29 PM writes...

The problem with the negative rules is that they can be self-reinforcing because people spend less time investigating the "riskier" areas which then makes them risky since there are no results to learn from. Eventually you just end up looking for your keys under the lamppost.

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7. Anonymous on January 6, 2014 8:09 PM writes...

@6: Precisely, and that's what's killing innovation: People telling you stuff will never work, without ever testing it.

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8. DevicesRus on January 7, 2014 11:22 AM writes...

In the medical device world there are so many urban legends around particular types of devices that innovation is extremely difficult. In my current job I spend at least 50% of my time telling the kids to "try it" even though many of the older engineers say that it can't work because something similar didn't work 15 years ago. What is interesting though is that different companies have very different sets of urban legends and many of those are in completely opposite directions.

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